Brinzolamide is a carbonic anhydrase inhibitor used to lower intraocular pressure in patients with ocular hypertension or open-angle glaucoma. Brinzolamide is chemically (R)-(+)-4-Ethylamino-2-(3-methoxypropyl)-3,4-dihydro-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide-1,1-dioxide and has the empirical formula C12H21N3O5S3. Brinzolamide has a molecular weight of 383.5 and a melting point of about 131.deg.C.
This compound is disclosed in U.S. Pat. No. 5,378,703 (Dean, et al.). The compound is also disclosed in European patent EP 527801. U.S. Pat. No. 6,071,904 discloses processes for preparation of brinzolamide ophthalmic composition.
Brinzolamide ophthalmic suspension is developed and marketed by Alcon Laboratories Inc. in United States under the brand name AZOPT® (Brinzolamide ophthalmic suspension 1%). Brinzolamide is indicated for lowering elevated intra-ocular pressure (TOP) in patients with open-angle glaucoma or ocular hypertension (OHT).
Various methods have been disclosed in the prior for the preparation of brinzolamide ophthalmic suspension. International patent application WO 98/25620 teaches that conventional sterilization methods cannot be employed in the manufacture of suspensions comprising brinzolamide since the compound recrystallizes at autoclaving temperatures forming large needle-type crystals.
According to WO 98/25620, also dry heat sterilization is not suitable since it causes melting of the material, whereas sterilization by ethylene oxide and gamma irradiation introduces unacceptable degradation products.
EP0941094 discloses a process for making brinzolamide suspension by autoclaving of concentrated slurry of brinzolamide in milling bottle, ball milling of the hot slurry, and then adding the slurry to the rest of the ingredients.
EP2394637 discloses a process for sterilizing brinzolamide suspensions using gamma irradiation or ethylene oxide.
In these cited references procedures, the use of a typical ball milling process to reduce particle size of ophthalmic drugs in aqueous suspensions is not desirable for several reasons. Firstly, the ball-milling process and parameters must be carefully controlled in order to ensure adequate particle size reduction.
Secondly, it was found that the ball-milling process does not prevent subsequent aggregation of the drug particles in the suspension formulation. As a result, the suspension formulation may contain drag aggregates having a particle sizes above the recommended range for ophthalmic formulations. Thus, formulations prepared according to WO 98/25620 may not have the desired stability towards drug particle aggregation.
Thus, a cited reference discloses autoclaving of the slurry of brinzolamide and surfactant and further ball milling the slurry. However, the drawback associated with this method is that it requires a milling bottles in which the slurry of brinzolamide could initially be autoclaved and then ball milled for further size reduction of needle shaped crystals of brinzolamide that are formed during autoclaving leading to wastage, expensive, time consuming and non-reproducible process. Furthermore the use of expensive instruments adds to the cost of production.
The inventors of the present invention have surprisingly invented a cost effective, easily reproducible process with minimal use of equipment's and complex technology for manufacturing a sterile ophthalmic suspension comprising sterile brinzolamide wherein the process does not require the use of any specific equipment's such as ball mill, milling bottle and/or jet mill. This process ameliorates the drawbacks associated with cited references methods for preparation of brinzolamide ophthalmic suspension.